WO2001010416A1 - Procede d'administration d'un agent chimiotherapeutique a une tumeur solide - Google Patents

Procede d'administration d'un agent chimiotherapeutique a une tumeur solide Download PDF

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Publication number
WO2001010416A1
WO2001010416A1 PCT/US2000/021919 US0021919W WO0110416A1 WO 2001010416 A1 WO2001010416 A1 WO 2001010416A1 US 0021919 W US0021919 W US 0021919W WO 0110416 A1 WO0110416 A1 WO 0110416A1
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Prior art keywords
tumor
microparticles
poly
carboplatin
polymer
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PCT/US2000/021919
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English (en)
Inventor
Raymond T. Bartus
Dwaine F. Emerich
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Alkermes Controlled Therapeutics, Inc.
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Priority to AU65364/00A priority Critical patent/AU6536400A/en
Publication of WO2001010416A1 publication Critical patent/WO2001010416A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • BBB blood brain barrier
  • Methods of treating brain tumors have included the delivery of chemotherapeutics directly to the surgical cavity resulting from surgical debulking of the tumor or intratumorally.
  • chemotherapeutics directly to the surgical cavity resulting from surgical debulking of the tumor or intratumorally.
  • the use of polymer wafers containing N,N ' -Bis(2-chloroethyl)-N-nitrosourea (BCNU) have shown limited efficacy in the treatment of gliomas when the wafers are placed in the surgical cavity resulting from a glioma debulking.
  • prostate cancer is a common form of cancer among males.
  • Clinical evidence shows that human prostate cancer has the propensity to metastasize to bone and is currently the second leading cause of cancer death, after lung cancer, among men.
  • treatment is based on surgery and/or radiation therapy, but these methods give unsatisfactory results in a significant percentage of cases.
  • breast cancer is the most common form of cancer in women in the United States. Both its cause and the means for its cure remain undiscovered. In 2000, 182,800 new cases of female invasive breast cancer are expected to be diagnosed, and 40,800 women are expected to die from the disease. Breast cancer is the second leading cause of cancer death for all women, and the leading overall cause of death in women between the ages of 40 and 55.
  • the present invention relates to a method of treating a patient suffering from a solid tumor, such as a tumor of the brain, prostate, breast, lung, colon, uterus, skin, liver, bone, pancreas, ovary, testes, bladder, kidney, head, neck, stomach, cervix, rectum, larynx, or esophagus.
  • the method comprises administering to the peritumoral tissue an effective amount of a sustained release composition comprising a biocompatible polymer and at least one chemotherapeutic agent dispersed within the polymer.
  • the sustained release composition is in the form of microparticles.
  • the microparticles can be administered by injection into peritumoral tissue.
  • the chemotherapeutic agent can be any agent which is therapeutically effective. Combinations of chemotherapeutic agents can also be present in the sustained release device.
  • the polymer of the sustained release composition can be any biocompatible polymer.
  • the polymer is biodegradable.
  • the administration of the sustained release composition into the peritumoral tissue rather than directly into the tumor provides increased therapeutic benefits, for example, increased survival.
  • administration can be accomplished by injection, resulting in a minimally invasive procedure.
  • Figure 1 is a plot of in vitro release of carboplatin from PLG microparticles containing carboplatin at loading densities of 10, 15 or 20%, versus time over a 21 day period.
  • Figure 2 is a plot of the in vitro cytotoxicity of RG2 cells following 72 hours of exposure to microparticles containing carboplatin, versus a bolus of carboplatin at the indicated doses.
  • Figure 3 A is a plot of the amount of carboplatin present in healthy brain tissue at 0-0.5 mm distance from the site of injection, following administration of microparticles containing carboplatin and an equivalent dose of a carboplatin bolus, versus time post administration.
  • Figure 3B is a plot of the amount of carboplatin present in healthy brain tissue at 0.5-1.5 mm distance from the site of injection, following administration of microparticles containing carboplatin and an equivalent dose of a carboplatin bolus, versus time post administration.
  • Figure 4 is a plot of the % survival for treatment groups receiving specified amounts of microparticles containing carboplatin, and a bolus injection of carboplatin directly into the center of an 8 day old striatal tumor, versus time post tumor implantation in days. The survival curve for animals with no treatment is also shown.
  • Figure 5 is a plot of the % survival for treatment groups receiving specified amounts of microparticles containing carboplatin, and a bolus injection of a carboplatin at three predetermined sites (triangle formation) of the peritumoral tissue. The survival curve for animals with no treatment is also shown.
  • Figure 6 is a plot of the % survival for treatment groups receiving specified amounts of microparticles containing BCNU, and a bolus injection of BCNU directly into the center of an 8 day old striatal tumor, versus time post tumor implantation in days. The survival curve for animals with no treatment is also shown.
  • Figure 7 is a plot of the % survival for treatment groups receiving specified amounts of microparticles containing BCNU, and a bolus injection of a BCNU at three predetermined sites (triangle formation) of the peritumoral tissue. The survival curve for animals with no treatment is also shown.
  • Figure 8 is a set of graphs showing the effects of bolus and sustained release carboplatin, injected either into the tumor center or into the peritumoral tissue, on the suppression of growth of MATB-III tumors implanted into the subcutaneous space of rats.
  • Figure 9 is a set of graphs showing the effects of bolus and sustained release 5-FU, injected either into the tumor center or the peritumoral tissue, on the suppression of growth of MATB-III tumors grown in the subcutaneous space of rats.
  • Figure 10 is a graph showing the effects of sequential injections into the peritumoral tissue (14 days following the first treatment) of sustained release carboplatin or 5FU microparticles on the growth of MATB-III tumors.
  • Solid tumor refers to any tumor which forms a mass.
  • solid tumors include, but are not limited to, tumors of the brain, prostate, breast, colon, lung, kidney, bladder, liver, bone, head, neck, stomach, larynx, esophagus, cervix, rectum, uterus, skin (e.g., melanomas), endometrium, pancreas and testes.
  • Brain tumor or “tumors of the brain”, as that term is used herein, refers to primary and metastatic brain tumors. Gliomas are primary brain tumors which arise from the glial cells in the brain and spinal cord, and are the most common primary brain tumors. Gliomas are classified into several groups based on the type of glial cell involved. For example, astrocytomas, which are the most common type of gliomas, are developed from astrocytes. Types of astrocytomas include well- differentiated, anaplastic, and glioblastoma multiforme.
  • glioma Other types include ependymomas, ohgodendrogliomas, ganglioneuromas, mixed gliomas, brain stem gliomas, optic nerve gliomas, meningiomas, pineal tumors, pituitary adenomas, and primitive neuroectodermal tumors, such as medulloblastomas, neuroblastomas, pineoblastomas, medulloepitheliomas, ependymoblastomas and polar spongioblastomas.
  • Non-glioma type tumors include chordomas and craniopharyngiomas .
  • the tumor is a deep, surgically-inoperable tumor.
  • a deep, surgically-inoperable glioma For example, a deep, surgically-inoperable glioma.
  • Administration into the tissue of the peritumoral area can be accomplished by a single administration, by multiple administrations into a single site, by multiple administrations into multiple sites or combinations thereof. Multiple injections can also be spread out over time for instance over days or weeks. Administration can be accomplished by, for example, injection or surgical implantation. For example, stereotactic injection or implantation is suitable. Importantly, administration is into the peritumoral area rather than directly into the tumor.
  • injection includes administration through a delivery port alone or in combination with a surgical scope such as a laparoscope, endoscope, laryngoscope, cystoscope, proctoscope or thoracoscope.
  • the delivery port can be, for example, a surgical tube such as a catheter with an appropriately sized bore, or a needle or needle-like port.
  • delivery can include a minor incision in the patient to permit entry of a delivery port, such as a needle or catheter, or a combination of a delivery port and a surgical scope.
  • injection of the composition avoids the need for an open surgical procedure to expose the treatment area.
  • Patient refers to the recipient of the treatment. Mammalian and non-mammalian patients are included. In a specific embodiment, the patient is a mammal, such as a human, canine, murine, feline, bovine, ovine, swine or caprine. In a preferred embodiment, the patient is a human.
  • Periodumoral area is the outermost edge or perimeter of the tumor and tissue which is within 3 cms outward of the outermost edge of the tumor, and 1 cm inward of the outermost edge. Preferably the area is within 2 cms outward of the outermost edge of the tumor and 1 cm inward of the outermost edge.
  • “Bolus injection”, as that term is used herein, is an injection of a solution of a chemotherapeutic agent which is not present in a sustained release composition.
  • sustained release composition as defined herein, comprises a biocompatible polymer having incorporated therein at least one chemotherapeutic agent.
  • Suitable biocompatible polymers can be either biodegradable or non- biodegradable polymers or blends or copolymers thereof, as described herein.
  • the sustained release composition can contain from about 0.01% (w/w) to about 50% (w/w) of the chemotherapeutic agent (dry weight of composition).
  • the amount of agent used will vary depending upon the desired effect of the agent, the planned release levels, and the time span over which the agent will be released.
  • a preferred range of agent loading is between about 0.1% (w/w) to about 30% (w/w) agent.
  • a more preferred range of agent loading is between about 0.5% (w/w) to about 20% (w/w) agent.
  • the sustained release compositions of this invention can be formed into many shapes such as a film, a pellet, a rod, a filament, a cylinder, a disc, a wafer or a microparticle.
  • a microparticle is preferred.
  • a "microparticle” as defined herein, comprises a polymer component having a diameter of less than about one millimeter and having a chemotherapeutic agent dispersed therein.
  • a microparticle can have a spherical, non-spherical or irregular shape.
  • the microparticle will be of a size suitable for injection.
  • a preferred size range for microparticles is from about one to about 180 microns in diameter.
  • a sustained release of chemotherapeutic agent is a release of the agent from a sustained release composition. The release occurs over a period which is longer than that period during which a therapeutically significant amount of the chemotherapeutic agent, would be available following direct administration of a solution of the chemotherapeutic agent. It is preferred that a sustained release be a release of chemotherapeutic agent which occurs over a period of greater than two days.
  • a sustained release of chemotherapeutic agent, from a sustained release composition can be a continuous or a discontinuous release, with relatively constant or varying rates of release. The continuity of release and level of release can be affected by the type of polymer composition used (e.g., monomer ratios, molecular weight, and varying combinations of polymers), agent loading, and/or selection of excipients to produce the desired effect.
  • a “therapeutically effective amount”, as used herein, is the amount of the composition for the sustained release of a chemotherapeutic agent, necessary to elicit the desired biological response following administration.
  • the desired biological response is prevention or reduction in the progression of a solid tumor, or reversal partially or totally of the developed solid tumor. It is understood that by treating the solid tumor that survival time of the patient en be prolonged. Dosage can be optimized depending on the size of the sustained release composition, the location and size of the solid tumor to be treated and the period over which the drug will be delivered.
  • Chemotherapeutic agents suitable for use in the invention include any chemotherapeutic.
  • Classes of chemotherapeutics include, but are not limited to, antimetabolites, cytotoxic agents, immunomodulators, antibiotic derivatives and nitrogen mustard derivatives, antiangiogenic agents, receptor antagonists, receptor ligands, stimulators, and viral vectors.
  • the chemotherapeutic agent has limited ability to cross the blood brain barrier. Combinations of chemotherapeutic agent can also be present in the sustained release composition.
  • Specific agents include, but are not limited to, carboplatin, cisplatin, adriamycin, doxorubicin, carmustine (also referred to in the art as N,N -Bis(2- chloroethyl)-N-nitrosourea, BCNU and BiCNU), lomustine (also referred to in the art as N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea and CCNU), etoposide, teniposide, 0 6 -benzylguanine, paclitaxel, methotrexate, vincristine, vinblastine, vinorelbine, gemcitabine, cyclophosphamide, temaso'amide, 5-fluorouracil and 4-
  • the sustained release composition can contain other biologically active agents which impart a beneficial effect.
  • anti-inflammatory agents, antibacterial agents and/or antiviral agents can be present in the composition.
  • the method described herein can be combined with other cancer therapies, such as, radiation therapy.
  • the chemotherapeutic agent of the sustained release composition can be stabilized against degradation, loss of potency and/or loss of biological activity, all of which can occur during formation of the sustained release composition and/or prior to and during in vivo release of the chemotherapeutic agent.
  • stabilization can result in a decrease in the solubility of a chemotherapeutic agent, the consequence of which is a reduction in the initial release of agent.
  • the period of release of the agent can be prolonged.
  • Stabilization of the chemotherapeutic agent can be accomplished, for example, by the use of a stabilizing agent.
  • "Stabilizing agent”, as that term is used herein, is any agent which binds or interacts in a covalent or non-covalent manner or is included with the chemotherapeutic agent. Stabilizing agents suitable for use in the invention are described in co-pending U.S. Patent Application 08/934,830 to Burke et al., filed on September 22, 1997 and U.S. Patent Nos.
  • a metal cation can be complexed with the chemotherapeutic agent, or the chemotherapeutic agent can be complexed with a polycationic complexing agent such as protamine, albumin, spermidine and spermine, or associated with a "salting-out" salt.
  • Suitable metal cations include any metal cation capable of complexing with the agent.
  • a metal cation-stabilized chemotherapeutic agent as defined herein, comprises a chemotherapeutic agent and at least one type of metal cation wherein the cation is not significantly oxidizing to the agent.
  • the metal cation is multivalent, for example, having a valency of +2 or more.
  • Suitable stabilizing metal cations include biocompatible metal cations.
  • a metal cation is biocompatible if the cation is non-toxic to the recipient, in the quantities used, and also presents no significant deleterious or untoward effects on the recipient's body, such as a significant immunological reaction at the injection site.
  • the suitability of metal cations for stabilizing chemotherapeutic agents and the ratio of metal cation to chemotherapeutic agent needed can be determined by one of ordinary skill in the art by performing a variety of stability indicating techniques, for example, HPLC analyses (e.g., Size Exclusion, Reversed Phase and other Ion Exchange) on particles of metal cation-stabilized chemotherapeutic agents.
  • the molar ratio of metal cation to agent is typically between about 1 :2 and about 100:1, preferably between about 2:1 and about 10:1.
  • stabilizing metal cations include, but are not limited to, K + , Zn +2 , Mg +2 and Ca +2 .
  • Stabilizing metal cations also include cations of transition metals, such as Cu +2 . Combinations of metal cations can also be employed.
  • the chemotherapeutic agent can also be stabilized with at least one polycationic complexing agent.
  • Suitable polycationic complexing agents include, but are not limited to, protamine, and albumin.
  • the suitability of polycationic complexing agents for stabilizing chemotherapeutic agents can be determined by one of ordinary skill in the art in the manner described above for stabilization with a metal cation. An equal weight ratio of polycationic complexing agent to chemotherapeutic agent is suitable.
  • a polymer is biocompatible if the polymer and any degradation products of the polymer are non-toxic to the recipient and also possess no significant deleterious or untoward effects on the recipient's body, such as a significant chronic immunological reaction at the injection site.
  • Biodegradable means the composition will degrade or erode in vivo to form smaller chemical species. Degradation can result, for example, by enzymatic, chemical and/or physical processes.
  • Suitable biocompatible, biodegradable polymers include, for example, poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid- co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polyacetals, polycyanoacrylates, polyamides, polyacetals, poly( ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blend
  • Biocompatible, non-biodegradable polymers suitable for use in the invention include, for example, polyacrylates, polymers of ethylene-vinyl acetates and acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, blends and copolymers thereof.
  • terminal functionalities or pendant groups of the polymers can be modified, for example, to modify hydrophobicity, hydrophilicity and/or provide, remove or block moieties which can interact with the active agent (via, for example ionic or hydrogen bonding).
  • Acceptable molecular weights for polymers used in this invention can be determined by a person of ordinary skill in the art taking into consideration factors such as the desired polymer degradation rate, physical properties such as mechanical strength, and rate of dissolution of polymer in solvent and viscosity. Typically, an acceptable range of molecular weight is about 2,000 Daltons to about 2,000,000 Daltons.
  • the polymer is a biodegradable polymer or copolymer.
  • the polymer is poly(lactide-co- glycolide) (hereinafter "PLG").
  • the sustained release composition can contain excipients. These excipients are added to maintain the potency of the chemotherapeutic agent over the duration of release and modify polymer degradation. Suitable excipients include, for example, carbohydrates, amino acids, fatty acids, surfactants, and bulking agents, and are known to those skilled in the art. The amount of excipient used is based on ratio to the chemotherapeutic agent, on a weight basis. For amino acids, fatty acids and carbohydrates, such as sucrose, lactose, mannitol, dextran and heparin, the ratio of carbohydrate to chemotherapeutic agent, is typically between about 1 :10 and about 20:1. For surfactants, such as TWEENTM and PLURONICTM, the ratio of surfactant to chemotherapeutic agent is typically between about 1 :1000 and about 1 :20.
  • excipients include, for example, carbohydrates, amino acids, fatty acids, surfactants, and bulking agents, and are known to those skilled in the art
  • Bulking agents typically comprise inert materials. Suitable bulking agents are known to those skilled in the art.
  • the excipient can also be a metal cation component which is separately dispersed within the polymer matrix.
  • This metal cation component acts to modulate the release of the chemotherapeutic agent, by for example, modifying polymer degradation and is not complexed with the chemotherapeutic agent.
  • the metal cation component can optionally contain the same species of metal cation, as is contained in the metal cation stabilized chemotherapeutic agent, and/or can contain one or more different species of metal cation.
  • the metal cation component acts to modulate the release of the chemotherapeutic agent from the polymer matrix of the sustained release composition and can enhance the stability of the chemotherapeutic agent in the composition.
  • a metal cation component used in modulating release typically comprises at least one type of multivalent metal cation.
  • metal cation components suitable to modulate release include or contain, for example, Mg(OH) 2 , MgCO 3 (such as 4MgCO 3 .Mg(OH) 2 .5H 2 O), MgSO 4 , Zn(OAc) 2 , Mg(OAc) 2 , ZnCO 3 (such as 3Zn(OH) 2 2ZnCO 3 ), ZnSO 4 , ZnCl 2 , MgCl 2 , CaCO 3 , zinc citrate and magnesium citrate.
  • a suitable ratio of metal cation component to polymer is between about 1 :99 to about 1 :2 by weight. The optimum ratio depends upon the polymer and the metal cation component utilized.
  • a polymer matrix containing a dispersed metal cation component to modulate the release of a biologically active agent from the polymer matrix is further described in U.S. Patent
  • At least one pore forming agent such as a water soluble salt, sugar or amino acid, is included in the sustained release composition to modify the microstructure.
  • the proportion of pore forming agent is between about
  • At least one pore forming agent be included in a nonbiodegradable polymer matrix of the present invention.
  • a number of methods are known by which compounds can be encapsulated in the form of microparticles.
  • the material to be encapsulated is dispersed in a solvent containing a wall forming material.
  • solvent is removed from the microparticles and thereafter the microparticle product is obtained.
  • organic solvent is evaporated from a dispersion of microparticles in an aqueous medium, preferably under reduced pressure.
  • a mixture comprising at least one chemotherapeutic agent, at least one biocompatible polymer and at least one polymer solvent is processed to create droplets, wherein at least a significant portion of the droplets contains polymer, polymer solvent and the agent.
  • droplets are then frozen by a suitable means.
  • means for processing the suspension to form droplets include directing the dispersion through an ultrasonic nozzle, pressure nozzle, Rayleigh jet, or by other known means for creating droplets from a solution.
  • Means suitable for freezing droplets include directing the droplets into or near a liquified gas, such as liquid argon or liquid nitrogen to form frozen microdroplets which are then separated from the liquid gas.
  • a liquified gas such as liquid argon or liquid nitrogen
  • the frozen microdroplets are then exposed to a liquid or solid non-solvent, such as ethanol, hexane, ethanol mixed with hexane, heptane, ethanol mixed with heptane, pentane or oil.
  • the solvent in the frozen microdroplets is extracted as a solid and or liquid into the non-solvent to form a polymer/chemotherapeutic agent matrix comprising a biocompatible polymer and a chemotherapeutic agent.
  • Mixing ethanol with other non-solvents, such as hexane, heptane or pentane, can increase the rate of solvent extraction, above that achieved by ethanol alone, from certain polymers, such as poly(lactide-co-glycolide) polymers.
  • a wide range of sizes of sustained release compositions can be made by varying the droplet size, for example, by changing the ultrasonic nozzle diameter. If the sustained release composition is in the form of microparticles, and very large microparticles are desired, the microparticles can be extruded, for example, through a syringe directly into the cold liquid. Increasing the viscosity of the polymer solution can also increase microparticle size. The size of the microparticles which can be produced by this process ranges, for example, from greater than about 1000 to about 1 micrometers in diameter.
  • Yet another method of forming a sustained release composition, from a suspension comprising a biocompatible polymer and a chemotherapeutic agent includes film casting, such as in a mold, to form a film or a shape. For instance, after putting the suspension into a mold, the polymer solvent is then removed by means known in the art, or the temperature of the polymer suspension is reduced, until a film or shape, with a consistent dry weight, is obtained.
  • the release of the chemotherapeutic agent can occur by two different mechanisms.
  • the agent can be released by diffusion through aqueous filled channels generated in the polymer matrix, such as by the dissolution of the agent, or by voids created by the removal of the polymer solvent during the preparation of the sustained release composition.
  • a second mechanism is the release of the agent, due to degradation of the polymer.
  • the rate of degradation can be controlled by changing polymer properties that influence the rate of hydration of the polymer. These properties include, for instance, the ratio of different monomers, such as lactide and glycolide, comprising a polymer; the use of the L-isomer of a monomer instead of a racemic mixture; and the molecular weight of the polymer.
  • hydrophilicity and crystallinity can affect hydrophilicity and crystallinity, which control the rate of hydrationof the polymer.
  • Hydrophilic excipients such as salts, carbohydrates, and surfactants can also be incorporated to increase hydration which can alter the rate of erosion of the polymer.
  • the contributions of diffusion and/or polymer degradation to agent release can be controlled. For example, increasing the glycolide content of a poly(lactide-co-glycolide) polymer and decreasing the molecular weight of the polymer can enhance the hydrolysis of the polymer, and thus provides an increased chemotherapeutic agent release from polymer erosion.
  • the rate of polymer hydrolysis is increased in non-neutral pH. Therefore, an acidic or a basic excipient can be added to the polymer suspension, used to form the sustained release composition, for example, microparticles, to alter the polymer erosion rate.
  • mice Male Fischer rats (170 - 220g; Taconic Farms, Germantown, NY) were used in all studies. The rats were housed in pairs in polypropylene cages with free access to food and water. The vivarium was maintained on a 12 h light: 12 h dark cycle with a room temperature of 22°C ⁇ 1, and relative humidity level of 50% ⁇ 5%. All procedures complied with NTH Guidelines.
  • EXAMPLE 1 TUMOR CELL IMPLANTATION Rat glioma (RG2) cells were maintained as a monolayer culture in F10 medium (GJJ3CO, Grant Island, NY) with iron supplemented 10% calf serum until confluent (3-5 days). On the day of implantation, the cells were suspended in F10 medium with 1.2% methylcellulose (Sigma, St. Louis, MO). Immediately prior to implantation of RG2 cells into the brain, rats were anesthetized using an intramuscular injection of a solution containing ketamine (24 mg/mL), xylazine (1.3 mg/mL) and acepromizine (0.33 mg/mL) and placed in a stereotaxic instrument.
  • F10 medium GJJ3CO, Grant Island, NY
  • iron supplemented 10% calf serum until confluent (3-5 days). On the day of implantation, the cells were suspended in F10 medium with 1.2% methylcellulose (Sigma, St. Louis, MO).
  • rats were anesthet
  • RG2 cells were injected unilaterally into the striatum (5xl0 4 cells/5 ⁇ L) at the following coordinates: A-P (+2.0 mm), L (+3.0 mm) and V (-6.5 mm).
  • EXAMPLE 2 FABRICATION AND IMPLANTATION OF CARBOPLATIN- LOADED PLG MICROPARTICLES
  • PLG (1.70 g) was dissolved in methylene chloride (3 g). To this solution was added 170 mg of ground/sieved carboplatin ( ⁇ 5 ⁇ m), and the mixture was shaken vigorously and sonicated. 100 mL of a 1 % PV A solution was then added and the mixture was homogenized at about 12,000 rpm for approximately 3 minutes.
  • the resulting suspension was then quickly heated in a water bath (approximately 50°C) with stirring at about 550 rpm. After 15 minutes, the carboplatin-containing microparticles were collected by filtration, sieved through 70 ⁇ m and 40 ⁇ m screens and rinsed with water. The microparticles were then frozen at -70°C and lyophilized under 50 ⁇ Torr for 2 days. Blank microparticles were prepared using the same procedure except that carboplatin was not present.
  • microparticles were suspended in a solution containing 0.9% saline, 0.5% Tween and 3.0% carboxymethylcellulose (low viscosity). All suspensions were prepared to yield a final concentration of 10%
  • EXAMPLE 5 IN VIVO RELEASE AND DIFFUSION FROM CARBOPLATIN- CONTALNLNG MICROPARTICLES
  • 1 mg of microparticles containing a 10% load of carboplatin 100 ⁇ g carboplatin
  • a separate series of animals received a bolus injection of carboplatin (100 ⁇ g) into the same site.
  • the brain tissue surrounding the needle tract was dissected into two discrete regions using microdissection techniques.
  • the first section extended from the needle tract outward for 0.5 mm, and the second section extended from 0.5 mm to 1.5 mm from the needle tract.
  • Tissue samples were digested in 0.5 ml of Soluene and incubated at 37°C for 8 hours. 0.5 mL of methylene chloride was then added to dissolve the microparticles and permit quantification of platinum levels. All tissue samples were frozen at ' 80°C, and platinum levels were determined by atomic adso ⁇ tion spectroscopy. The results are represented graphically in Figure 3.
  • the model of glioma used in these studies determined the effects of sustained release of carboplatin from the microparticles containing carboplatin on survival of animals bearing deep, surgically-inoperable tumors.
  • the carboplatin- containing microparticles were implanted directly into a growing tumor, and also into the peritumoral tissue.
  • RG2 cells were implanted unilaterally into the striatum.
  • the animals received implants of microparticles containing carboplatin or a bolus injection of carboplatin directly into the tumor. All injections, which were made directly into the tumor, used the same coordinates for implantation of the RG2 cells (A-P (+2.0 mm), L (+3.0 mm) and V (-6.6 mm)).
  • implants were made at 3 sites surrounding the tumor which correspond to the following coordinates: A-P (+2.85 mm), L (+3.0 mm) and V (-5.5 mm); A-P (+1.15 mm), L (+2.0 mm) and V (-5.5 mm); A-P (+1.5 mm), L (+4.0 mm) and V (-5.5 mm).
  • the total dose for each treatment group was equally divided among the three sites.
  • the solution was added to a 100 mL 4-necked glass reaction flask contained 40 mL of 0.75% PVA solution mechanically stirred (Caframo, model RZR1, Wiarton, Ont., Canada).
  • the organic phase was then dispersed in aqueous medium.
  • the temperature was maintained at room temperature for 10 minutes, gradually raised to 40°C for 50 minutes by a circulating water bath and maintained at 40°C for an additional 50 minutes.
  • the suspension was drained from the flask and the microparticles were collected by filtration.
  • the microcapsules were sieved through 70 and 40 ⁇ m cell strainers, and the 40-70 ⁇ m sized fraction was collected and washed with distilled water.
  • the microparticles were then frozen at -
  • Blank (noncarmustine-loaded) microspheres were treated in an identical manner except that carmustine was omitted from the procedure.
  • EXAMPLE 8 IMPLANTATION OF BCNU-CONTAINTNG MICROPARTICLES
  • EXAMPLE 9 CELL MAINTENANCE AND IMPLANTATION OF MATB-III CELLS MATB-III cells, originally derived from a rat mammary carcinoma (ATCC# CRL-1666), were grown and maintained as a suspension culture in McCoy's 5 A Medium supplemented with 10% fetal bovine serum, 20mM HEPES and l/2x penicillin-streptomycin/fungizone. Cells were harvested and centrifuged at 1500g for 4 minutes at 10 °C prior to suspending at a density of 2 x 10 cells/mL in HEPES-buffered serum-free media containing 1.2% methyl cellulose. For implantation, rats were briefly anesthetized with a combination of O 2 /CO 2 .
  • MATB- i ⁇ cells (lxl0 6 cells/200 ⁇ L) were injected subcutaneously into the right rear flank using a 21 gauge needle attached to a 1 mL syringe. All tumors were allowed to grow for 7 days at which time animals with tumors that had reached a size of approximately 140 mm 2 were used in dosing studies. Tumors were measured every 2-4 days and any animal bearing a tumor equal to or greater than 900 mm 2 was sacrificed.
  • EXAMPLE 10 PREPARATION OF CARBOPLATIN LOADED AND 5-FU LOADED MICROPARTICLES
  • Carboplatin loaded and blank microparticles were prepared according to Example 2, with a carboplatin loading density of 10% (w/w).
  • Microparticles containing 5-fluorouracil at a loading density of 10% (w/w) were also prepared according to the method described in Example 2.
  • EXAMPLE 11 BOLUS CHEMOTHERAPY AND IMPLANTATION OF SUSTAINED RELEASE CHEMOTHERAPEUTIC MICROPARTICLES IN A RAT MODEL OF SOLID TUMOR
  • mice received injections of microparticles containing carboplatin or 5-FU (10% w/v) prepared as described above, or a bolus injection of carboplatin or 5-FU, directly into the center of the tumor or into the peritumoral tissue.
  • Microparticles were formulated to release carboplatin or 5-FU in a sustained fashion over about a two week period.
  • Bolus injections into the center of the tumor were made in a volume of 150 ⁇ L using a 20 gauge needle attached to a 200 ⁇ L Hamilton syringe.
  • mice received the same total amount of carboplatin or 5-FU that was injected into the center of the tumor, except that it was equally divided into 6 separate 25 ⁇ L aliquots.
  • sustained release microparticles a total of 50 mg of microparticles were suspended (30% PLG w/v) in a solution of 0.9% saline, 0.1% Tween and 3.0% carboxymethylcellulose (low viscosity).
  • Animals receiving injections into the center of the tumor received 150 ⁇ L of the suspension, while animals receiving microparticles within the peritumoral tissue received the same total amount of sustained release carboplatin or 5-FU that was delivered directly into the center of the tumor, except that it was equally divided into separate 25 ⁇ L aliquots for each of the 6 injection sites.
  • the injection sites were determined by first making a small incision in the skin overlying the tumor. Once the peripheral tumor was visualized, microparticles were injected into six discrete sites as follows: Four sites equally distributed along the equator of the tumor and one site at each of the two distal poles of the tumor.
  • microparticles were injected using a 20 gauge needle as described above.
  • animals received a total of 0.1, 0.5, 1.0, or 5.0 mg of carboplatin or 5-FU. Control animals received either no treatment or blank microparticles. Identical amounts of microparticles were injected in all cases by adding blank microparticles to the suspension. The different treatment groups and the numbers of animals in each are listed below in Table 3. TABLE 3
  • the animal were again injected (21 days post implantation) into the peritumoral tissue as described above with carboplatin or 5-FU containing microparticles.
  • Figure 10 is a graph of the effect of this sequential administration on tumor growth. A further reduction in tumor growth was observed for both the carboplatin and 5-FU sustained release compositions following a second peritumoral injection of microparticles containing either carboplatin or 5-FU. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

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Abstract

L'invention concerne un procédé permettant de traiter un patient souffrant d'une tumeur solide, par exemple une tumeur cérébrale, une tumeur du sein, une tumeur de la prostate, etc., chirurgicalement inopérables, qui consiste à administrer au tissu péritumoral une dose efficace d'une composition à libération durable contenant un polymère biocompatible et au moins un agent chimiothérapeutique dispersé à l'intérieur du polymère.
PCT/US2000/021919 1999-08-11 2000-08-10 Procede d'administration d'un agent chimiotherapeutique a une tumeur solide WO2001010416A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007915A2 (fr) * 2001-07-19 2003-01-30 Guilford Pharmaceuticals, Inc. Compositions permettant le traitement de cancers de la tete et du cou, et procedes de fabrication et d'utilisation associes
EP1668424A2 (fr) * 2003-09-12 2006-06-14 Trustee for the Bankruptcy Estate of Ferx, Inc. Peters, Stephen Particules ciblables magnetiquement contenant des composes magnetiques et des polymeres biocompatibles pour l'administration specifique de sites d'agents actifs biologiquement
US8987339B2 (en) 2013-03-14 2015-03-24 Medicus Biosciences Llc Solid polyglycol-based biocompatible pre-formulation
US9072809B2 (en) 2012-05-11 2015-07-07 Medical Biosciences Llc Biocompatible hydrogel treatments for retinal detachment
US9271931B2 (en) * 2001-10-03 2016-03-01 Celator Pharmaceuticals, Inc. Compositions for delivery of drug combinations
WO2017053811A1 (fr) * 2015-09-25 2017-03-30 Provista Diagnostics, Inc. Biomarqueurs pour la détection du cancer du sein chez les femmes ayant des seins denses
US10058507B2 (en) 2001-10-03 2018-08-28 Celator Pharmaceuticals, Inc. Compositions for delivery of drug combinations
US10111985B2 (en) 2011-08-10 2018-10-30 Medicus Biosciences, Llc Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules
US10189773B2 (en) 2010-05-07 2019-01-29 Medicus Biosciences, Llc In-vivo gelling pharmaceutical pre-formulation
US11083821B2 (en) 2011-08-10 2021-08-10 C.P. Medical Corporation Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0145240A2 (fr) * 1983-11-04 1985-06-19 Takeda Chemical Industries, Ltd. Méthode de préparation de microcapsules
US5688530A (en) * 1989-07-07 1997-11-18 Novartis Ag Sustained release formulations of water soluble peptides
WO1997042940A1 (fr) * 1996-05-14 1997-11-20 Alkermes Controlled Therapeutics, Inc. Procede de preparation de dispositifs a liberation retardee a base de polymeres
WO2000041678A1 (fr) * 1999-01-11 2000-07-20 Guilford Pharmaceuticals Inc. Procedes de traitement du cancer des ovaires, compositions poly(phosphoester), et articles biodegradables a cet effet

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0145240A2 (fr) * 1983-11-04 1985-06-19 Takeda Chemical Industries, Ltd. Méthode de préparation de microcapsules
US5688530A (en) * 1989-07-07 1997-11-18 Novartis Ag Sustained release formulations of water soluble peptides
WO1997042940A1 (fr) * 1996-05-14 1997-11-20 Alkermes Controlled Therapeutics, Inc. Procede de preparation de dispositifs a liberation retardee a base de polymeres
WO2000041678A1 (fr) * 1999-01-11 2000-07-20 Guilford Pharmaceuticals Inc. Procedes de traitement du cancer des ovaires, compositions poly(phosphoester), et articles biodegradables a cet effet

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007915A3 (fr) * 2001-07-19 2003-04-24 Guilford Pharm Inc Compositions permettant le traitement de cancers de la tete et du cou, et procedes de fabrication et d'utilisation associes
WO2003007915A2 (fr) * 2001-07-19 2003-01-30 Guilford Pharmaceuticals, Inc. Compositions permettant le traitement de cancers de la tete et du cou, et procedes de fabrication et d'utilisation associes
US10722464B2 (en) 2001-10-03 2020-07-28 Celator Pharmaceuticals, Inc. Compositions for delivery of drug combinations
US9271931B2 (en) * 2001-10-03 2016-03-01 Celator Pharmaceuticals, Inc. Compositions for delivery of drug combinations
US10058507B2 (en) 2001-10-03 2018-08-28 Celator Pharmaceuticals, Inc. Compositions for delivery of drug combinations
EP1668424A2 (fr) * 2003-09-12 2006-06-14 Trustee for the Bankruptcy Estate of Ferx, Inc. Peters, Stephen Particules ciblables magnetiquement contenant des composes magnetiques et des polymeres biocompatibles pour l'administration specifique de sites d'agents actifs biologiquement
EP1668424A4 (fr) * 2003-09-12 2009-11-25 Onkor Pharmaceuticals Inc Particules ciblables magnetiquement contenant des composes magnetiques et des polymeres biocompatibles pour l'administration specifique de sites d'agents actifs biologiquement
US10227289B2 (en) 2010-05-07 2019-03-12 Medicus Biosciences, Llc Methods for treating diseases of the lung
US10189773B2 (en) 2010-05-07 2019-01-29 Medicus Biosciences, Llc In-vivo gelling pharmaceutical pre-formulation
US10111985B2 (en) 2011-08-10 2018-10-30 Medicus Biosciences, Llc Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules
US11083821B2 (en) 2011-08-10 2021-08-10 C.P. Medical Corporation Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules
US11596710B2 (en) 2012-05-11 2023-03-07 C.P. Medical Corporation Biocompatible hydrogel treatments for retinal detachment
US9623144B2 (en) 2012-05-11 2017-04-18 Medicus Biosciences Llc Biocompatible hydrogel treatments for retinal detachment
US9072809B2 (en) 2012-05-11 2015-07-07 Medical Biosciences Llc Biocompatible hydrogel treatments for retinal detachment
US10507262B2 (en) 2012-05-11 2019-12-17 C.P. Medical Corporation Biocompatible hydrogel treatments for retinal detachment
US9149560B2 (en) 2013-03-14 2015-10-06 Medicus Biosciences Llc Solid polyglycol-based biocompatible pre-formulation
US8987339B2 (en) 2013-03-14 2015-03-24 Medicus Biosciences Llc Solid polyglycol-based biocompatible pre-formulation
WO2017053811A1 (fr) * 2015-09-25 2017-03-30 Provista Diagnostics, Inc. Biomarqueurs pour la détection du cancer du sein chez les femmes ayant des seins denses
CN108738346A (zh) * 2015-09-25 2018-11-02 普罗维斯塔诊断公司 用于检测具有致密的乳腺的女性中的乳腺癌的生物标志

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